The risk of coronary heart disease (CHD) in systemic lupus erythematosus (SLE) women is up to 50 times higher than in the general population. The conventional risk factors are insufficient to explain premature CHD in SLE patients. Compared to about 1-5 percent prevalence of antiphospholipid antibodies (APA) in the general U.S. white population, about 50 percent of the SLE patients are positive for APA. ApoH is a principal autoantigen for the production of APA in patients with autoimmune diseases. ApoH inhibits the in vitro uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, but in the presence of APA it promotes the ihflux of oxLDL into macrophages. As the accumulation of oxLDL in macrophages is believed to initiate the atherosclerotic process, these findings suggest that apoH-mediated immune response in patients with autoimmune diseases, like SLE, may lead to atherosclerosis. In this renewal we propose to examine the joint roles of APA, antibodies to oxLDL (anti-oxLDL) and APOH genetic variation (known and discovered as part of this proposal) in relation to the occurrence of CHD in SUE and non-SLE patients. Our hypothesis is that individuals positive for APA and/or anti-oxLDL are prone to premature CHD and this susceptibility is modified by common genetic variation in the APOH gene. The objectives of the study will be achieved by fulfilling the five aims. Aim 1) identify and characterize naturally occurring common mutations in all exons, introns and the 3' region of the APOH gene by polymerase chain reaction (PCR), denaturing HPLC analysis and DNA sequencing in SLE and non-SLE CHD patients, and African blacks positive for APA. Aim 2) determine the prevalence and correlation between APA (anti-apoH, anticardiolipin, lupus anticoagulant) and anti-oxLDL in plasma samples from SLE patients and controls. Aim 3) determine the relationship between APOH genetic variation (data generated in Aim 1) and the occurrence of APA and anti-oxLDL (data generated in Aim 2). Aim 4) examine the relationship between APOH genetic variation (data generated in Aim 1) and the occurrence of subclinical cardiovascular events in SLE patients and with coronary atherosclerosis in non-SLE patients. Aim 5) perform in vitro mutagenesis and expression studies to express different apoH allelic-isoforms to evaluate isoform-specific inhibition of LDL oxidation.